The proposed project, Neuropathology of CTE and Late Effects of TBI: Toward In-Vivo Diagnostics is a multi- center and multi-disciplinary study designed to dramatically increase our understanding of chronic traumatic encephalopathy (CTE) and other late effects of traumatic brain injury (TBI). TBI is a major public health concern in the US, as the current prevalence of TBI in the US is unprecedented. Some TBI survivors experience particularly poor outcomes as they age; these include accelerated cognitive and health decline, dementia, and in some cases, CTE. CTE is thought to be a tauopathy but has been described only in convenience samples of people with repetitive head trauma. CTE is incompletely described in individuals with mild, moderate and severe TBI. The population incidence and prevalence, risk factors, and causal role of multifocal tauopathy on associated symptoms are unknown. Overlapping clinical features, postmortem pathologies and patterns of involvement exist in TBI, CTE, and Alzheimer's disease pose challenges to accurate diagnosis. Premortem diagnosis of CTE is currently impossible. The neuropathological consequences of single mild or moderate-severe TBI and its relationship with CTE and known dementias are unclear. The proposed project will leverage extensive resources from an ongoing population-based prospective cohort study of brain aging (Adult Changes in Thought; ACT, n=2,305) which includes excellent medical, behavioral, and genetic characterization of a cohort (20% of whom have a history of mild-moderate TBI) in addition to state-of-the-art neuropathology workup upon death. Neuropathological study of TBI effects can begin immediately in the existing ACT autopsy sample (n=489, 20% with TBI exposure). Additional cohorts of TBI- exposed individuals will come from the Brain Injury Research Center at Mount Sinai (n=150 individuals with moderate-severe TBI), the University of Texas Southwestern (n=50 retired boxers with repetitive TBI exposure), and the National Football League (n=76 retired players with repetitive TBI exposure). All participants in the proposed study (ACT and other sites) will undergo uniform harmonized neurobehavioral assessment (chosen to maximize correspondence with existing large-scale TBI and dementia studies), MRI scan, and genomic analysis. Those individuals who expire during the course of the study will undergo ex-vivo neuroimaging and extensive neuropathological exam using state-of-the-art techniques (such as Histelide) designed to quantify tau and A in whole brain specimens. Only by examining postmortem pathology in a sample of individuals with varying levels of TBI exposure who are well characterized during life (as proposed herein) can postmortem pathology facilitate identification of in-vivo biomarkers that can act as diagnostic tools. This project represents the most systematic and scientifically rigorous effort to date to develop a more complete understanding of the long-term clinical and neuropathological sequelae of single and multiple TBI.